3-aminochroman spiro compounds

ABSTRACT

The invention relates to a compound selected from those of formula (I):    &lt;IMAGE&gt;  (I)  in which R1, R2, R3, A and m are as defined in the description. Medicinal product which is useful for treating depression and anxiety.

CROSS-REFERENCE

This application is a division of Ser. No. 08/036,329, filed Mar. 24,1993, U.S. Pat. No. 5,397,783.

The present invention relates to new 3-aminochroman spiro compounds, toprocesses for their preparation and to pharmaceutical compositionscontaining them.

3-Aminochroman, 3-aminothiochroman and some of their derivatives areknown to be ligands for the receptors of the central nervous system,more particularly of the serotoninergic system, and this makes themusable for the treatment of anxiety, of depression and more particularlyof disorders of the central nervous system (European Patents EP 279,150and EP 222,996). The compounds described in these patents have a certainaffinity for the 5-HT_(1A) receptors but also for the D2 receptors, andthis results in very low selectivity.

Spiro compounds derived from 2-aminotetralin (a) (J. Med. Chem. (1978)21 (6) pp 585-7 and J. Pharm. Pharmacol. (1976) 28 suppl. pp 83 P) andfrom 3-amino-quinoline (b) (Patent FR 2,255,067 and Yakugaku Zasshi(1974) 94 (12) pp 1566-73) are also known in the literature ##STR2##

These compounds are described above all as antalgic, spasmolytic andantihistaminic agents, with, in the case of the tetralin compounds, alsoa very slight antidepressant component.

Spiro[pyrrolidine-2,3 '-chroman] (c) also described in the literature,without any information other than its structure. ##STR3##

The compounds of the present invention, which are 3-aminochroman spirocompounds, apart from the fact that their structures are new, haveremarkable pharmacological properties.

These compounds are, in fact, powerful ligands for 5-HT_(1A) receptors.This high affinity is all the more interesting since it is backed by ahigh selectivity in favor of 5-HT_(1A) receptors when compared withdopaminergic and alpha adrenergic receptors and with otherserotoninergic receptors (5-HT_(1B), 5-HT_(1C), 5-HT_(1D), 5-HT₂).

These remarkable pharmacological properties render the compounds of thepresent invention usable in the treatment of disorders of the centralnervous system, especially of the serotoninergic system, such asdepression, stress, psychosis, anxiety, schizophrenia, as well as ofpain, migraines, hypertension and cerebral ischemia. These compounds mayalso be of interest as modifiers of the alimentary and sexual behavior.

More specifically, the present invention relates to the compounds ofgeneral formula (I): ##STR4## in which: m, an integer, can assume thevalues 1 or 2,

A denotes a methylene (CH₂) or a carbonyl (CO),

R₁ denotes:

a hydrogen,

a group --CO--R₄ with R₄ denoting a linear or branched alkyl with 1 to 6carbon atoms, an optionally substituted phenyl or an optionallysubstituted phenylalkyl whose alkyl chain contains from 1 to 3 carbonatoms,

or a linear or branched alkyl with 1 to 6 carbon atoms, optionallysubstituted by:

a nitrile,

an optionally substituted phenyl,

a group --NR₅ R₆ with R₅ denoting a hydrogen or a linear or branchedalkyl with 1 to 6 carbon atoms and R₆ denoting a hydrogen, a linear orbranched alkyl with 1 to 6 carbon atoms, optionally substituted by anoptionally substituted phenyl, a linear or branched alkylcarbonyl groupcontaining from 2 to 7 carbon atoms, an optionally substituted benzoylgroup, an optionally substituted phenylalkylcarbonyl group whose alkylchain contains from 1 to 3 carbon atoms, a linear or branchedalkylsulfonyl group with 1 to 6 carbon atoms, or an optionallysubstituted phenylsulfonyl group,

any one of the following groups: ##STR5## in which: X and Y, which areidentical or different, denote a hydrogen, a halogen, a hydroxyl, alinear or branched alkyl with 1 to 4 carbon atoms, a linear or branchedalkoxy with 1 to 4 carbon atoms,

n, an integer, can assume the values 1 or 2

R2 denotes:

a hydrogen,

an acetyl group,

a CF₃ SO₂ --O-- group

or a group --OR₇ with R₇ having the same definition as R₁,

R₃ denotes a hydrogen or a linear or branched alkyl with 1 to 4 carbonatoms, provided that when R₁ =R₂ =R₃ =H then m cannot be equal to 1,

the expression "optionally substituted" associated with the phenyl,phenylalkyl, phenylsulfonyl, benzoyl or phenylalkylcarbonyl terms meansthat the aromatic nucleus may be substituted by one or a number of loweralkyls with 1 to 4 carbon atoms, branched or otherwise, nitro, loweralkoxy with 1 to 4 carbon atoms, halogen, trifluoromethyl or hydroxyl,

their isomers, diastereoisomers and enantiomers, isolated or in mixtureform,

their salts of addition to a pharmaceutically acceptable inorganic ororganic acid.

The invention also extends to the process for obtaining the compounds ofgeneral formula (Ia): ##STR6## in which R₁, R₂ and R₃ are as defined informula (I), a particular case of the compounds of formula (I) in whichcompounds m is equal to 1 and A denotes a carbonyl (CO), wherein asubstituted benzaldehyde of general formula (II): ##STR7## in which R₈denotes a hydrogen or a linear or branched alkoxy with 1 to 6 carbonatoms is reacted at a temperature of between -5° and 0° C., with borontribromide so as to obtain the compound of general formula (III):##STR8## in which R₈ has the same meaning as above, which is reactedwith heating and in the presence of a substituted ammonium salt with2-nitroethanol, so as to obtain the compound of general formula (IV):##STR9## in which R₈ has the same meaning as above, which is reduced soas to obtain the compound of general formula (V): ##STR10## in which R₈has the same meaning as above, which is reacted in the presence ofbenzyltrimethylammonium methylate in alcoholic medium with an acryliccompound of general formula (VI): ##STR11## in which R₃ has the samemeaning as above and Alk denotes an alkyl with 1 to 4 carbon atoms, soas to obtain the compounds of general formula (VIIa): ##STR12## in whichR₃, R₈ and Alk have the same meaning as above, which is reduced in thepresence of Raney nickel and under hydrogen atmosphere so as to obtain,after isolation and optional purification, the spiro compound of generalformula (VIIIa): ##STR13## in which R₃ and R₈ have the same meaning asabove, which can be reacted in the presence of a strong base with acompound of general formula (IX):

    Hal'R'.sub.1                                               (IX)

in which R'₁ has the same meaning as R₁ in formula (I), provided thatR'₁ cannot denote a hydrogen, and Hal' denotes a halogen atom, so as toobtain, after isolation and optional purification, the compound ofgeneral formula (Xa): ##STR14## in which R'₁, R₃ and R₈ have the samemeaning as above, compounds of formula (VIIIa) and (Xa) which may betreated, in the case where R₈ denotes an alkoxy, with an aqueoussolution containing hydrobromic acid, to obtain, after isolation andoptional purification, the compound of general formula (XIa): ##STR15##in which R'₁ and R₃ have the same meaning as above, which can be reactedwith a compound of general formula (XII):

    Hal"--R'.sub.7                                             (XII)

in which Hal" denotes a halogen atom and R'₇ has the same meaning as R₇in formula (I), provided that R'₇ cannot denote a hydrogen, so as toobtain, after isolation and optional purification, the compound ofgeneral formula (XIIIa): ##STR16## in which R'₁, R₃ and R'₇ have thesame meaning as above, it being understood that the compounds of generalformula VIIIa, Xa, XIa and XIIIa form part of the invention, constitutethe compounds of general formula (Ia) such as are defined above, andcan, if desired, be purified, separated into their isomers, or, ifpossible, converted into salts with a pharmaceutically acceptable acid.

The invention also extends to the process for obtaining the compounds ofgeneral formula (Ib): ##STR17## in which R₁, R₂ and R₃ are as defined informula (I), a particular case of the compounds of formula (I) in whichcompounds m is equal to 2 and A denotes a carbonyl (CO), wherein acompound of formula (V): ##STR18## in which R₈ denotes a hydrogen or alinear or branched alkoxy with 1 to 6 carbon atoms is reacted with ahalo ester of general formula (X): ##STR19## in which R₃ has the samemeaning as above, Alk denotes an alkyl with 1 to 4 carbon atoms and Haldenotes a halogen atom, so as to obtain the compounds of general formula(VIIb): ##STR20## in which R₃, R₈ and Alk have the same meaning asabove, which are reduced, in the presence of Raney nickel and underhydrogen atmosphere, so as to obtain, after isolation and optionalpurification, the spiro compound of general formula (VIIIb): ##STR21##in which R₃ and R₈ have the same meaning as above, which can be reactedin the presence of a strong base with a compound of general formula(IX):

    Hal'R'.sub.1

in which R'₁ has the same meaning as R₁ in formula (I), provided thatR'₁ cannot denote a hydrogen and Hal' denotes a halogen atom, so as toobtain, after isolation and optional purification, the compound ofgeneral formula (Xb): ##STR22## in which R'₁, R₃ and R₈ have the samemeaning as above, compounds of formula (VIIIb) and (Xb) which mayoptionally be treated, in the case where R₈ denotes an alkoxy, with anaqueous solution containing hydrobromic acid, to obtain, after isolationand optional purification, the compound of general formula (XIb):##STR23## in which R'₁ and R₃ have the same meaning as above, which canbe reacted with a compound of general formula (XII):

    Hal"--R'.sub.7                                             (XlI)

in which Hal" denotes a halogen atom and R'₇ has the same meaning as R₇in formula (I), provided that R'₇ cannot denote a hydrogen, so as toobtain, after isolation and optional purification, the compound ofgeneral formula (XIIIb): ##STR24## in which R'₁, R₃ and R'₇ have thesame meaning as above, it being understood that the compounds of generalformula VIIIb, Xb, XIb and XIIIb form part of the invention, form thecompounds of general formula (Ib) such as are defined defined above, andcan, if desired, be purified, separated into their isomers, or, ifpossible, converted into salts with a pharmaceutically acceptable acid.

The invention also extends to the process for obtaining the compounds ofgeneral formula (Ic): ##STR25## in which R₁, R₂, R₃ and m are as definedin formula (I), a particular case of the compounds of formula (I) inwhich compounds A denotes a methylene (CH₂), wherein a compound offormula (VIII): ##STR26## in which R₃ and m are as defined above and R₈denotes a hydrogen or a linear or branched alkoxy with 1 to 6 carbonatoms, is reduced in aprotic medium by a reducing agent, so as toobtain, after isolation and optional purification, the compound ofgeneral formula (XIV): ##STR27## in which R₃, R₈ and m have the samemeaning as above, which can be reacted with a compound of generalformula (IX):

    Hal'R'.sub.1                                               (IX)

in which R'₁ has the same meaning as R₁ in formula (I), provided thatR'₁ cannot denote a hydrogen and Hal denotes a halogen atom, so as toobtain, after isolation and optional purification, the compound ofgeneral formula (XV): ##STR28## in which R'₁, R₃, R₈ and m have the samemeaning as above, compounds of formula (XIV) and (XV) which can betreated, in the case where R₈ denotes an alkoxy, with an aqueoussolution containing hydrobromic acid, to obtain, after isolation andoptional purification, the compound of general formula (XVI): ##STR29##in which R'₁, R₃ and m have the same meaning as above, which can bereacted with a compound of general formula (XII):

    Hal"--R'.sub.7                                             (XII)

in which Hal" denotes a halogen atom and R'₇ has the same meaning as R₇in formula (I), provided that R'₇ cannot denote a hydrogen, so as toobtain, after isolation and optional purification, the compound ofgeneral formula (XVII): ##STR30## in which R'₁, R₃, R'₇ and m have thesame meaning as above, it being understood that the compounds of generalformula XIV, XV, XVI and XVII form part of the invention, constitute thecompounds of general formula (Ic) and can, if desired, be purified,separated into their isomers or, if possible, converted into salts witha pharmaceutically acceptable acid.

The invention also extends to the process for obtaining the compounds ofgeneral formula (Id): ##STR31## in which R₁, R₃ and m are as defined informula (I), a particular case of the compounds of formula (I) in whichcompounds R₂ denotes an acetyl group, wherein a compound of generalformula (XVIII): ##STR32## in which R₁, R₂ and m are as defined above,is reacted with trifluoromethanesulfonic anhydride so as to obtain thetrifluoromethylsulfonyloxy compound of general formula (XIX): ##STR33##in which R₁, R₃ and m have the same definition as above, which is nexttreated in aprotic medium with butyl vinyl ether in the presence oftriethylamine, of 1,2-bis(diphenylphosphino)ethane and of Pd(OAc)₂ so asto obtain, after isolation and purification, the acetylated compound ofgeneral formula (XX): ##STR34## in which R₁, R₃ and m have the samemeaning as above, it being understood that the compounds of generalformula XIX and XX form part of the invention and can, if desired, bepurified, separated into their isomers or, if possible, converted intosalts with a pharmaceutically acceptable acid.

The compounds of general formula (I) and their salts of addition to apharmaceutically acceptable inorganic or organic acid, are powerfulligands for 5-HT_(1A) receptors, with an agonist or antagonist activityin the central nervous system.

This high affinity which is backed by a very high selectivity for thesereceptors in relation to the D₂, α₂ receptors and to the otherserotoninergic receptors renders these compounds of great interest forthe treatment of stress, of anxiety, of depression, of psychosis, ofschizophrenia, of pain, of cardiovascular disorders, of hypertension, ofmigraines and of cerebral ischemia.

They can also modify alimentary and sexual behavior.

The compounds of general formula (I) and their salts of addition to apharmaceutically acceptable inorganic or organic acid, such as, forexample, hydrochloric, methanesulfonic, nitric, maleic and similaracids, can be presented in the form of pharmaceutical compositions,using known processes, such as, for example: tablets, gelatin tablets,coated pills, injectable solutions, drinkable solutions or suspensions,emulsions and suppositories.

Besides the inert, nontoxic and pharmaceutically acceptable excipientssuch as, for example, distilled water, glucose, lactose, starch, talc,vegetable oils, ethylene glycol and the like, these compositions mayalso contain preserving agents.

The pharmaceutical compositions thus obtained also form part of theinvention and, depending on the disorders being treated, the age and theweight of the patient, may contain from 0.1 to 100 mg of activesubstance in the case of a treatment with 1 to 3 doses per 24 hours.

The following examples illustrate the invention and do not limit it inany way.

PREPARATION 1: N-(4-BROMOBUT-1-YL)-8-AZASPIRO[4,5]DECANE-7,9-DIONE

Add 7.43 g (53.8 mmol) of potassium carbonate, 4.26 g (19.73 mmol) of1,4-dibromobutane and a catalytic quantity of potassium iodide to asolution of 3 g (17.94 mmol) of 8-azaspiro[4,5]decane-7,9-dione.

Heat to 60° C. for 6 hours and then cool and remove acetonitrile byevaporation at reduced pressure.

After hydrolysis with 10 cm³ of water, extract the product withmethylene chloride and then, after drying and final drying, purify thecrude product by chromatography on a silica column (eluent: methylenechloride).

N-(4-Bromobut-1-yl)-8-azaspiro[4,5]decane-7,9-dione is finally obtainedin the form of oil in a yield of 69%.

Infrared (film): 1660 and 1720 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR35## 1.45 to 1.52, multiplet, 4H, 2CH₂ 1.45 to 1.52, multiplet, 6H, 3 CH₂

1.79 to 1.90, multiplet, 2H, H_(c)

2.60, singlet, 4H, H_(e)

3.42, triplet J=7.1 Hz, 2H, Ha

3.80, triplet J=7.1 Hz, 2H, Hd

PREPARATION 2 AND 3

By proceeding in the same way as in the case of preparation 1 butreplacing 1,4-dibromobutane with:

1,5-dibromobutane, N-(5-bromopent-1-yl)-8-azaspiro[4,5]decane-7,9-dioneis obtained in a yield of 50%.

Infrared (film): 1655 and 1715 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR36## 1.35 to 1.73, multiplet, 12H, 6CH₂ 1.81 to 1.90, multiplet, 2H, CH₂

2.57, singlet, 4H, Hf

3.38, triplet J=7.1 Hz, 2H, Ha

3.74, triplet J=7.1 Hz, 2H, He

1,3-dibromopropane, N-(3-bromoprop-1-yl)-8-azaspiro[4,5]decane-7,9-dioneis obtained in a yield of 70%.

Infrared (film): 1665 and 1720 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR37## 1.45 to 1.56, multiplet, 4H, 2CH₂ 1.66 to 1.75, multiplet, 4H, 2 CH₂

2.06 to 2.15, multiplet, 2H, Hb

2.59, singlet, 4H, Hd

3.36, triplet J=7.1 Hz, 2H, Ha

3.89, triplet J=7.1 Hz, Hc

PREPARATION 4: N-(2-BROMOETHYL)-8-AZASPIRO[4,5]DECANE-7,9-DIONE

Add 0.65 g (26.9 mmol) of sodium hydride to a solution of 3 g (17.94mmol) of 8-azaspiro[4,5]decane-7,9-dione in 30 cm³ of anhydrousN,N-dimethylformamide.

Stir at 60° C. for 1 hour then add 20.21 g (107.6 mmol) of1,2-dibromoethane and a catalytic quantity of potassium iodide.

Continue heating for one hour after the addition and then, aftercooling, remove the solvent at reduced pressure and then, after aqueoushydrolysis, extract the product with methylene chloride and purify thecrude product obtained by chromatography on a silica column.

N-(2-Bromoethyl)-8-azaspiro[4,5]decane-7,9-dione is thus obtained in ayield of 63%.

Infrared (film): 1660 and 1715 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR38## 1.46 to 1.54, multiplet, 4H, 2CH₂ 1.67 to 1.76, multiplet, 4H, 2 CH₂

2.62, singlet, 4H, H_(c)

3.48, triplet J=6.9 Hz, 2H, Ha

4.20, triplet J=6.9 Hz, 2H, Hb

PREPARATIONS 5 TO 7

By proceeding in the same way as in the case of preparation 1 butreplacing 8-azospiro[4,5]decane-7,9-dione with:

1,1-dioxo-1,2-benzisothiazol-3(2H)-one,N-(4-bromo-butyl)-1,1-dioxo-1,2-benzisothiazol-3(2H)-one is obtained ina yield of 60%.

Infrared (film): 1720 cm⁻¹ ν C=O

1300 and 1170 cm⁻¹ ν SO₂

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR39## 1.95 to 2.05, multiplet, 4H, Hband Hc 3.44, triplet J=7.1 Hz, 2H, Ha

3.82, triplet J=7.1 Hz, 2H, Hd

7.78 to 8.05, multiplet, 4H aromatic

2,4-dioxo-3-azabicyclo[3.3.0]octane,N-(4-bromobutyl)-3-azabicyclo[3.3.0]octane-2,4-dione is obtained in ayield of 58%.

Infrared (film): 1685 and 1760 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR40## 1.15 to 1.38, multiplet, 2H,CH₂ 1.62 to 2.14, multiplet, 8H, 4 CH₂

3.08 to 3.17, multiplet, 2H, H_(e)

3.38, triplet J=6.6 Hz, 2H, Ha

3.48, triplet J=6.6 Hz, 2H, Hd

4,4-dimethylpiperidine-2,6-dione,N-(4-bromobutyl)-4,4-dimethylpiperidine-2,6-dione is obtained in a yieldof 65%.

Infrared (film): 1660 and 1715 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR41## 1.06, singlet, 6H, Hf 1.61 to1.73, multiplet, 2H, CH₂

1.80 to 1.91, multiplet, 2H, CH₂

2.51, singlet, 4H, He

3.41, triplet J=6.3 Hz, 2H, Ha

3.80, triplet J=6.3 Hz, 2H, Hd

PREPARATIONS 8 AND 9

By proceeding in the same way as in the case of preparation 4, butreplacing 1,2-dibromobutane with 1,4-dibromobutane and8-azaspiro[4,5]decane-7,9-dione with:

3-azabicyclo[3.3.0]octan-2-one,N-(4-bromobutyl)-3-azabicyclo[3.3.0]octan-2-one is obtained in a yieldof 52%.

Infrared (film): 1670 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR42## 1.40 to 2.29, multiplet, 10H,5CH₂ 2.70 to 2.95, multiplet, 2H, CH₂

3.00, split doublet J₁ =9.7 Hz J₂ =2.6 Hz, Hf

3.20 to 3.40, multiplet, 2H, CH₂

3.44, triplet J=6.5 Hz, 2H, Ha

3.58, triplet J=9.7 Hz, 1H, Hg

oxazolo[4,5-b]pyridin-2(3H)-one,N-(4-bromobutyl)oxazolo[4,5-b]pyridin-2(3H)-one is obtained in a yieldof 64%.

Infrared (film): 1775 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR43## 2.41 to 2.51, multiplet, 4H, Hband Hc 3.47, triplet J=6.7 Hz, 2H, Ha

4.10, triplet J=6.7 Hz, 2H, Hd

7.08, split doublet J₁ =8 Hz J₂ =5.1 Hz, 1H, pyridine

7.41, doublet J=8 Hz, 1H, pyridine

8.11, doublet J=5.1 Hz, 1H, pyridine

PREPARATION 10: N-[(3-BROMOPROPYL)OXY]-8-AZASPIRO[4,5]-DECANE-7,9-DIONE

This compound is prepared, in a yield of 68% from8-hydroxy-8-azaspiro[4,5]decane-7,9-dione using the method described byNicholas J. Hrib et al. (J. Med. Chem. (1991) 34 1068).

Infrared (film): 1690 and 1740 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR44## 1.51 to 1.61, multiplet, 4H, 2CH₂ 1.68 to 1.78, multiplet, 4H, CH₂

2.21 to 2.28, multiplet, 2H, Hb

2.68, singlet, 4H, Hd

3.65, triplet J=6.3 Hz, 2H, Ha

4.12, triplet J=6.3 Hz, 2H, Hc

EXAMPLE 1: SPIRO[(5-METHOXYCHROMAN)-3,2'-(PYRROLIDIN-5'-ONE)] Stage I:Methyl 3-(5-methoxy-3-nitrochroman-3-yl)-propionate

Add 0.4 cm³ of benzyltrimethylammonium methylate and 5.16 cm³ of methylacrylate to a solution of 4 g (0.019 mol) of 5-methoxy-3-nitrochroman in60 cm³ of methanol.

The reaction mixture is stirred at 70° C. for 90 minutes and then cooledand concentrated at reduced pressure.

Add 30 cm³ of water and extract with methylene chloride.

The crude product obtained by removal of methylene chloride is purifiedby chromatography on a silica column (eluent: 50 methylene chloride/50petroleum ether).

5.1 g (90%) of methyl 3-(5-methoxy-3-nitro-chroman-3-yl)propionate arethus obtained in the form of colorless oil.

Infrared (film): 1730 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR45## 2.15 to 2.59, multiplet, 4H, Haand Hb 2.91, doublet J=17.5 Hz, 1H, H₄

3.57, doublet J=17.5 Hz, 1H, H₄

3.68, singlet, 3H, Hc

3.84, singlet, 3H, Hd

4.10 and 4.57, 2 doublets J=11.6 Hz, 2H, H₂

6.48 and 6.51, 2 doublets J=8.3 Hz, 2H, H aromatic

7.11, triplet J=8.3 Hz, 1H, H aromatic

Stage II: Spiro[(5-methoxychroman)-3,2'-(pyrrolidin-5'-one)]

Heat a solution of 5.1 g (0.017 mol) of methyl3-(5-methoxy-3-nitrochroman-3-yl)propionate in 100 cm³ of methanol at60° C. for 20 hours under hydrogen atmosphere in the presence of 0.715 gof Raney nickel.

After removal of the catalyst by filtation, the methanolic solution isheated to reflux for 4 hours.

After cooling and drying, the crude product obtained is purified bychromatography on a silica column (eluent: 80 methylene chloride/20methanol).

3.66 g (91%) of spiro[(5-methoxychroman)-3,2'-(pyrrolidin-5'-one)] arethus obtained in the form of a white solid.

Melting point: 210° C.

Infrared (KBr): 3250 cm⁻¹ ν NH

1670 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR46## 1.94 to 2.16, multiplet, 2H, H₃' 2.43 to 2.59, multiplet, 2H, H₄ '

2.75 and 2.87, 2 doublets J=16.5 Hz, H₄

3.83, singlet, 3H, Ha

3.89 and 3.94, 2 doublets J=11 Hz, H₂

5.83, unresolved bands, 1H, NH

6.46 and 6.53, 2 doublets J=8.3 Hz, 2H, H aromatic

7.11, triplet J=8.3 Hz, 1H, H aromatic

EXAMPLE 2: SPIRO[CHROMAN-3,2'-(PYRROLIDIN-5'-ONE)]

By proceeding as in Example 1 but replacing 5-methoxy-3-nitrochromanwith 3-nitrochroman in stage I, spiro[chroman-3,2'-(pyrrolidin-5'-one)]is obtained in a yield of 96%.

Melting point: 179° C.

Infrared (KBr): 3225 cm⁻¹ ν NH

1675 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR47## 1.91 to 2.17, multiplet, 2H, H₃' 2.51, triplet J=8.2 Hz; 2H, H₄ '

2.88 and 2.97, 2 doublets J=16.4 Hz, 2H, H₄

3.94 and 3.98, 2 doublets J=10.3 Hz, 2H, H₂

6.04, unresolved bands, 1H, NH

6.83 to 7.18, multiplet, 4H, H aromatic

EXAMPLE 3: SPIRO[(5-METHOXYCHROMAN)-3,2'-(N-PROPYLPYRROLIDIN-5'-ONE)]

Add 1 g (4.29 mmol) ofspiro[(5-methoxychroman)-3,2'-(pyrrolidin-5'-one)] in solution in 2 cm³of DMF to a suspension of 0.113 g (4.71 mmol) of sodium hydride in 18cm³ of DMF.

Stir at 60° C. for one hour and then add 3.61 g (0.021 mmol) of1-iodopropane. Continue heating for 8 hours and then cool and remove thesolvent at reduced pressure.

Add 10 cm³ of water and extract with methylene chloride.

The crude product obtained by drying the methylene chloride is purifiedby chromatography on a silica column (eluent: 50 ethyl ether/50methylene chloride).

Spiro[(5-methoxychroman)-3,2'-(N-propylpyrrolidin-5'-one)] is thusobtained in the form of white crystals in a yield of 64%.

Melting point: 90° C.

Infrared (KBr): 1670 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR48## 0.88, triplet J=8.5 Hz, 3H, Hc1.50 to 1.66, multiplet, 2H, Hb

1.74 to 1.84 and 2.07 to 2.16, 2 multiplets, 2H, H₃ '

2.44, triplet J=8.1 Hz, 2H, H₄ '

2.69, pair of doublets J=17.1 Hz, J=2.4 Hz, 1H, H₄

2.90, doublet J=17.1 Hz, 1H, H₄

3 to 3.23, multiplet, 2H, H_(a)

3.84, singlet, 3H, H_(d)

3.88, pair of doublets J=10.3 Hz, J=2.4 Hz, 1H, H₂

3.97, doublet J=10.3 Hz, 1H, H₂

6.48 and 6.52, 2 doublets J=8.3 Hz, 2H, H aromatic

7.11, triplet J=8.3 Hz, 1H, H aromatic

EXAMPLE 4: SPIRO[(5-METHOXYCHROMAN)-3,2'-PYRROLIDINE]

Add 0.35 cm³ of borane-dimethyl sulfide complex (2M) to a solution of0.1 g (0.42 mmol) of spiro[(5-methoxychroman)-3,2'-(pyrrolidin-5'-one)]in 5 cm³ of THF.

Heat the reaction mixture to reflux for 4 hours, dry under reducedpressure and take up the crude reaction product with 10 cm³ of 2Mhydrochloric acid and 5 cm³ of methanol.

The solution is heated to reflux for 90 minutes and then made basic witha 2M aqueous sodium hydroxide solution and extracted with methylenechloride.

After drying, the methylene chloride phase is dried and the crudeproduct purified by chromatography on a silica column (eluent: 95methylene chloride/5 methanol).

70 mg (76%) of spiro[(5-methoxychroman)-3,2'-pyrrolidine] are obtainedin the form of oil.

Infrared (film): 3300 cm⁻¹ ν NH

1585 cm⁻¹ ν C=C aromatic

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR49## 1.56 to 1.95, multiplet, 4H, H₄' and H₃ ' 2.21, singlet, 1H, NH

2.68, singlet, 2H, H₄

2.96 to 3.17, multiplet, 2H, H₅ '

3.80, singlet, 3H, Ha

3.82, singlet, 2H, H₂

6.43 and 6.52, 2 doublets J=8.3 Hz, 2H, H aromatic

7.06, triplet J=8.3 Hz, 1H, H aromatic

EXAMPLE 5: SPIRO[(5-METHOXYCHROMAN)-3,2'-(N-PROPYLPYRROLIDIN)]

Add 0.23 g (1.37 mmol) of 1-iodopropane and 0.19 g (1.37 mmol) ofpotassium carbonate to a solution of 0.1 g (0.456 mmol) ofspiro[(5-methoxychroman)-3,2'-pyrrolidine].

Heat to 60° C. for 3 hours, cool, remove the solvent at reducedpressure, hydrolyze and extract the aqueous phase with methylenechloride.

After drying, the crude product obtained is purified by chromatographyon a silica column (eluent: 20 ethyl ether/80 petroleum ether).

Spiro[(5-methoxychroman)-3,2'-(N-propylpyrrolidine)] is thus obtained ina yield of 84%.

Melting point (oxalate): 62° C.

Infrared (film): 2960 to 2800 cm⁻¹ ν CH

1585 cm⁻¹ ν C=C aromatic

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR50## 0.90, triplet, J=7.4 Hz, 3H, Hc1.42 to 1.97, multiplet, 6H, H₃ ', H₄ ', H_(b)

2.38 to 2.61, multiplet, 3H, H_(a), H₄

2.70, doublet J=17 Hz, 1H, H₄

2.82 to 3.03, multiplet, 2H, H₅ '

3.78, doublet J=10.3 Hz, 1H, H₂

3.81, singlet, 3H, H_(d)

3.83, doublet J=10.3 Hz, 1H, H₂

6.42 and 6.48, 2 doublets J=8.3 Hz, 2H, H aromatic

7.06, triplet J=8.3 Hz, 1H, H aromatic

EXAMPLE 6: SPIRO[CHROMAN-3,2'-(N-PROPYLPYRROLIDINE)]

By proceeding as in Example 5 but replacingspiro[(5-methoxychroman-3,2'-pyrrolidine] withspiro[chroman-3,2'-(N-propylpyrrolidine)],spiro[chroman-3,2'-(N-propylpyrrolidine)] is obtained in a yield of 61%.

Melting point (oxalate): 48° C.

Infrared (film): 2800 to 2980 cm⁻¹ ν CH

1575 cm⁻¹ ν C=C aromatic

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR51## 0.91, triplet, J=7.4 Hz, 3H,H_(c) 1.43 to 2.01, multiplet, 6H, H_(b), H₃ ', H₄ '

2.39 to 2.59, multiplet, 3H, H_(a), H₄

2.83 to 2.96, multiplet, 2H, H₅ '

3.02, doublet J=16.1 Hz, 1H, H₄

3.83, pair of doublets J=10.3 Hz J=2.4 Hz, 1H, H₂

3.88, doublet J=10.3 Hz, 1H, H₂

6.78 to 7.11, multiplet, 4H, H aromatic

EXAMPLE 7: SPIRO[(5-HYDROXYCHROMAN)-3,2'-(N-PROPYLPYRROLIDINE)]

Add 11 cm³ of hydrobromic acid at a concentration of 48% in water to asolution of 1.1 g (4.2 mmol) ofspiro[(5-methoxychroman)-3,2'-(N-propylpyrrolidine)] in 22 cm³ of aceticacid.

The reaction mixture is heated to reflux for 5 hours and then cooled,dried at reduced pressure, taken up with 40 cm³ of a saturated aqueoussolution of sodium bicarbonate and extracted with methylene chloride.

The crude product obtained by drying the methylene chloride is purifiedby chromatography on a silica column (eluent: 50 ethyl ether/50petroleum ether).

0.91 g (88%) of spiro[(5-hydroxychroman)-3,2'-(N-propylpyrrolidine)] arethus obtained.

Melting point (base): 185°-186° C.

Melting point (oxalate salt): 98° C. Infrared (KBr): 3250 cm⁻¹ (broadband) ν OH

¹ H NMR 300 MHz (DMSO-d₆) δ: ppm ##STR52## 0.83, triplet, J=7.4 Hz, 3H,H_(c) 1.30 to 1.45, multiplet, 3H, H_(b), H₃ '

1.65 to 1.80, multiplet, 3H, H₃ ', H₄ '

2.32, doublet J=17 Hz, 1H, H₄

2.39 to 2.53, multiplet, 2H, H_(a)

2.59, doublet J=17 Hz, 1H, H₄

2.71 to 2.90, multiplet, 2H, H₅ '

3.69 and 3.76, 2 doublets J=10.3 Hz, 2H, H₂

6.21 and 6.32, 2 doublets J=8.3 Hz, 2H, H aromatic

6.81, triplet J=8.3 Hz, 1H, H aromatic

9.32, singlet, 1H, OH

EXAMPLE 8:SPIRO[(5-METHOXYCHROMAN)-3,2'-{N-[4'-(8'-AZASPIRO[4',5']DECANE-7',9'-DION-8'-YL)-n-BUT-1'-YL]PYRROLIDINE}]

Add 1.82 g (6.02 mmol) ofN-(4-bromobut-1-yl)-8-azaspiro[4,5]decane-7,9-dione, 1.66 g (16.41 mmol)of triethylamine and a catalytic quantity of potassium iodide to asolution of 1.2 g (5.47 mmol) ofspiro[(5-methoxychroman)-3,2'-pyrrolidine] in 10 cm³ ofN,N-dimethylformamide.

The reaction mixture is heated to 60° C. for 8 hours, then cooled,concentrated at reduced pressure, taken up with 10 cm³ of water andextracted with methylene chloride.

The residual oil obtained by drying is purified by chromatography on asilica column (eluent: 50 methylene chloride/50 ethyl ether).

1.3 g (54%) ofspiro[(5-methoxychroman)-3,2'-{N-[4'-(8'-azaspiro[4',5']decane-7',9'-dion-8'-yl)-n-but-1'-yl]pyrrolidine}]are thus obtained.

Melting point (oxalate): 68° C.

Infrared (film): 1665 and 1720 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR53## 1.35 to 1.95, multiplet, 16H, 8CH₂ 2.40 to 2.56, multiplet, 3H, H₄ and H_(a)

2.57, singlet, 4H, H_(e)

2.66, doublet J=16.8 Hz, 1H, H₄

2.76 to 3.03, multiplet, 2H, H₅ '

3.69 to 3.79, multiplet, 4H, H_(d) and H₂

3.81, singlet, 3H, H_(f)

6.41 and 6.46, 2 doublets J=8.3 Hz, 2H, H aromatic

7.04, triplet J=8.3 Hz, 1H, H aromatic

EXAMPLE 9:SPIRO[CHROMAN-3,2'-{N-[4'-(8'-AZASPIRO[4',5']DECANE-7',9'-DION-8'-YL)-n-BUT-1'-YL]PYRROLIDINE}]

By proceeding as in Example 8, but replacingspiro[(5-methoxychroman)-3,2'-pyrrolidine] withspiro[chroman-3,2'-pyrrolidine],spiro[chroman-3,2'-{N-[4'-(8'-azaspiro[4',5']decane-7',9'-dion-8'-yl)-n-but-1'-yl]pyrrolidine}]is obtained in a yield of 55%.

Melting point (oxalate): 66° C.

Infrared (film): 1715 and 1660 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR54## 1.40 to 2, multiplet, 16H, 8CH₂ 2.44, doublet J=16.1 Hz, 1H, H₄

2.48 to 2.56, multiplet, 2H, Ha

2.58, singlet, 4H, He

2.79 to 2.96, multiplet, 2H, H₅ '

3.0, doublet J=16.1 Hz, 1H, H₄

3.73 to 3.91, multiplet, 4H, H₂ and Hd

6.77 to 7.10, multiplet, 4H, H aromatic

EXAMPLE 10:SPIRO[{5-[4-(8-AZASPIRO[4,5]DECANE-7,9-DION-8-YL)-n-BUT-1-YL]OXYCHROMAN}-3,2'-(N-PROPYLPYRROLIDINE)]

Add 0.076 g (0.25 mmol) ofN-(4-bromobut-1-yl)-8-azaspiro[4,5]decane-7,9-dione, 0.095 g (0.69 mmol)of potassium carbonate and a catalytic quantity of potassium iodide to asolution of 0.058 g (0.23 mmol) ofspiro-[(5-hydroxychroman)-3,2'-(N-propylpyrrolidine)] in 3 cm³ ofN,N-dimethylformamide.

Heat to 60° C. for 2 hours, cool, concentrate at reduced pressure andthen take up the crude reaction product in 10 cm³ of water and extractwith methylene chloride.

The crude oil obtained is purified by chromatography on silica column(eluent: 50 ethyl ether/50 methylene chloride).

Spiro[{5-[4-(8-azaspiro[4,5]decane-7,9-dion-8-yl)-n-but-1-yl]oxychroman}-3,2'-(N-propylpyrrolidine)]is thus obtained in the form of oil in a yield of 79%.

Melting point (oxalate): 68° C.

Infrared (film): 1660 and 1715 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR55## 0.94, triplet J=7.4 Hz, 3H,H_(c) 1.48 to 2.03, multiplet, 18H, 9 CH₂

2.40 to 2.68, multiplet, 7H, H_(h), H₄ and H_(a)

2.74, doublet J=17 Hz, 1H, H₄

2.90 to 3.06, multiplet, 2H, H₅ '

3.82 to 3.92, multiplet, 4H, H_(g) and H₂

3.95 to 4.04, multiplet, 2H, H_(d)

6.41 and 6.48, 2 doublets J=8.3 Hz, 2H, H aromatic

7.04, triplet J=8.3 Hz, 1H, H aromatic

EXAMPLES 11 AND 12

By proceeding in the same way as in Example 10 but replacingN-(4-bromo-n-but-1-yl)-8-azaspiro[4,5]-decane-7,9-dione with:

N-(4-bromo-n-but-1-yl)-4,4-dimethylpiperidine-2,6-dione,spiro[{5-[4-(4,4-dimethylpiperidine-2,6-dione-1-yl)-n-but-1-yl]oxychroman}-3,2'-(N-propyl-pyrrolidine)]is obtained ##STR56##N-(4-bromo-n-but-1-yl)-3-azabicyclo[3.3.0]octane-2,4-dione,spiro[{5-[4-(3-azabicyclo[3.3.0]octane-2,4-dione-3-yl)-n-but-1-yl]oxychroman}-3,2'-(N-propylpyrrolidine)]is obtained. ##STR57##

EXAMPLES 13 TO 32

By proceeding in the same way as in Example 8, but replacingN-(4-bromobut-1-yl)-8-azaspiro[4,5]decane-7,9-dione with:

N-(4-bromobutyl)phthalimide,spiro[(5-methoxy-chroman)-3,2'-N-(4'-phthalimido-n-but-1'-yl)pyrrolidine]]is obtained ##STR58##

Infrared (film): 1700 cm⁻¹ ν C=O

N-(3-bromopropyl)phthalimide,spiro[(5-methoxy-chroman)-3,2'-[N-(3'-phthalimidoprop-1'-yl)pyrrolidine]]is obtained

N-(3-bromoprop-1-yl)-8-azaspiro[4,5]decane-7,9-dione,spiro[(5-methoxychroman)-3,2'-{N-[3'-(8'-azaspiro[4',5']decane-7',9'-dion-8'-yl)-n-prop-1'-yl]pyrrolidine}]is obtained ##STR59##N-(5-bromopent-1-yl)-8-azaspiro[4,5]decane-7,9-dione,spiro[(5-methoxychroman)-3,2'-{N-[5'-(8'-azaspiro-[4',5']decane-7',9'-dion-8'-yl)-n-pent-1'-yl]prrolidine})]is obtained ##STR60## N-(2-bromoethyl)-8-azaspiro[4,5]decane-7,9-dione,spiro[(5-methoxychroman)-3,2'-{N-[2'-(8'-azaspiro[4',5']decane-7',9'-dion-8'-yl)-ethyl]pyrrolidine}]is obtained ##STR61##N-[(3-bromopropyl)oxy]-8-azaspiro[4,5]decane-7,9-dione,spiro[(5-methoxychroman)-3,2'-{N-[3'-(8'-azaspiro[4',5']decane-7',9'-dion-8'-yl)oxy-n-prop-1-yl]pyrrolidine}]is obtained ##STR62## N-(4-bromobutyl)oxazolo[4,5-b]pyridin-2(3H)-one,spiro[(5-methoxychroman)-3,2'-{N-[4'-(oxazolo[4',5'-b]pyridin-2'-(3H)-on-3'-yl)-n-but-1'-yl]pyrrolidine}]is obtained ##STR63## N-(4-bromobutyl)oxazolo[5,4-b]pyridin-2(3H)-one,spiro[(5-methoxychroman)-3,2'-{N-[4'-(oxazolo[5',4'-b]pyridin-2'(3H)-on-3'-yl)-n-but-1'-yl]pyrrolidine}]is obtained ##STR64##N-(4-bromobutyl)-3-azabicyclo[3.3.0]octane-2,4-dione,spiro[(5-methoxychroman)-3,2'-{N-[4'-(3'-azabicyclo[3.3.0]octane-2,4-dion-3-yl)-n-but-1'-yl]pyrrolidine}] isobtained ##STR65## N-(4-bromobutyl)-4,4-dimethylpiperidine-2,6-dione,spiro[(5-methoxychroman)-3,2'-{N-[4'-(4',4'-dimethylpiperidine-2',6'-dion-1'-yl)-n-but-1'-yl]-pyrrolidine}]is obtained ##STR66## N-(4-bromobutyl)benzoxazolin-2-one,spiro[(5-methoxychroman)-3,2'-{N-[4'-(benzoxazolin-2'-on-3'-yl)-n-but-1'-yl]pyrrolidine}]is obtained ##STR67##N-(4-bromobutyl)-1,1-dioxo-1,2-benzisothiazol-3(2H)-one,spiro[(5-methoxychroman)-3,2'-{N-[4'-(1',1'-dioxo-1',2'-benzisothiazol-3'(2H)-on-2'-yl)-n-but-1'-yl]pyrrolidine}]is obtained ##STR68## N-(4-bromobutyl)-3-azabicyclo[3.3.0]octan-2-one,spiro[(5-methoxychroman)-3,2'-{N-[4'-(3'-azabicyclo[3.3.0]octan-2'-on-3'-yl)-n-but-1'-yl]pyrrolidine}]is obtained ##STR69## N-(4-bromobut-1-yl)piperidin-2-one,spiro[(5-methoxychroman)-3,2'-{N-[4'-(piperidin-2'-on-1'-yl)-n-but-1'-yl]pyrrolidine}]is obtained ##STR70## benzyl bromide,spiro[(5-methoxychroman)-3,2'-(N-benzylpyrrolidine)] is obtained##STR71## 3,4-difluorobenzyl bromide,spiro[(5-methoxychroman)-3,2'-[N-(3',4'-difluorobenzyl)pyrrolidine]] isobtained

4-trifluoromethylbenzyl bromide,spiro[(5-methoxychroman)-3,2'-[N-(4'-trifluoromethylbenzyl)pyrrolidine]]is obtained

4-methylbenzyl bromide,spiro[(5-methoxychroman)-3,2'-[N-(4'-methylbenzyl)pyrrolidine]] isobtained

phenethyl bromide,spiro[(5-methoxychroman)-3,2'-(N-phenethylpyrrolidine)] is obtained

3-bromopropylbenzene,spiro[(5-methoxychroman)-3,2'-[N-(3'-phenyl-n-prop-1'-yl)pyrrolidine]]is obtained. ##STR72##

EXAMPLE 33:SPIRO[(5-METHOXYCHROMAN)-3,2'-[N-(2'-AMINOETHYL)PYRROLIDINE]] Stage I:Spiro[(5-methoxychroman)-3,2'-(N-cyanomethylpyrrolidine)]

Add 0.905 g (12 mmol) of chloroacetonitrile, 1.66 g (12 mmol) ofpotassium carbonate and a catalytic quantity of potassium iodide to asolution of 0.89 g (4.05 mmol) of spiro[(5-methoxychroman)-3,2'-pyrrolidine].

Heat to 60° C. for 20 hours then cool, concentrate at reduced pressure,take up with water and then extract with methylene chloride.

The crude product obtained after drying the methylene chloride phase ispurified by chromatography on a silica column (eluent: 99 methylenechloride/1 methanol).

Spiro[(5-methoxychroman)-3,2'-(N-cyanomethyl-pyrrolidine)] is thusobtained in a yield of 75%.

Stage II: Spiro[(5-methoxychroman)-3,2'-[N-(2'-aminoethyl)pyrrolidine]]

Slowly add 5.6 mmol of LiAlH₄ to a solution, under argon atmosphere, of0.72 g (2.8 mmol) ofspiro[(5-methoxychroman)-3,2'-(N-cyanomethylpyrrolidine)] in 20 cm³ oftetrahydrofuran.

Stir at room temperature for 30 minutes then cool with ice and hydrolyzewith 7 cm³ of iced water.

The organic phase is separated off, dried, and the crude productobtained purified by chromatography on a silica column (eluent: 99methylene chloride/1 methanol).

Spiro[(5-methoxychroman)-3,2'-[N-(2'-aminoethyl)pyrrolidine]] is thusobtained in a yield of 70%.

¹ NMR 300 MHz (CDCl₃) δ: ppm ##STR73## 1.45 to 1.90, multiplet, 4H, H₃ 'and H₄ ' 2.41 to 2.75, multiplet, 6H, H₄, H_(a), H_(b)

2.95, multiplet, 2H, H₅ '

3,80 to 3.85, multiplet singlet, 7H, H_(c), H₂ and NH₂

6.40 and 6.5, 2 doublets J=8 Hz, 2H, H aromatic

7.05, triplet J=8 Hz, 1H, H aromatic

EXAMPLE 34:SPIRO[(5-METHOXYCHROMAN)-3,2'-[N-(4'-AMINO-n-BUT-1'-YL)PYRROLIDINE]]Stage 1:Spiro[(5-methoxychroman)-3,2'-[N-(3'-cyano-n-prop-1'-yl)pyrrolidine]]

By proceeding as in Example 33 stage I but replacing chloroacetonitrilewith 4-bromobutyronitrile,spiro[(5-methoxychroman)-3,2'-[N-(3'-cyano-n-prop-1'-yl)pyrrolidine]] isobtained. ##STR74##

Stage II:Spiro[(5-methoxychroman)-3,2'-[N-(4'-amino-n-but-1'-yl)pyrrolidine]]

By reducingspiro[(5-methoxychroman)-3,2'-[N-(3-cyano-n-prop-1-yl)pyrrolidine]]under the conditions of Example 33 stage II,spiro[(5-methoxychroman)-3,2'-[N-(4'-amino-n-but-1'-yl)pyrrolidine]] isobtained. ##STR75##

EXAMPLE 35:SPIRO[(5-METHOXYCHROMAN)-3,2'-[N-(2'-para-TOLUENESULFONYLAMINOETHYL)PYRROLIDINE]]

Add dropwise 1.2 g (11.4 mmol) of triethylamine and then 0.8 g (5.8mmol) of tosyl chloride in solution in methylene chloride to a solutionof 1 g (3.8 mmol) ofspiro[(5-methoxychroman)-3,2'-[N-(2'-aminoethyl)pyrrolidine]] in 30 cm³of methylene chloride at 0° C.

After 30 minutes' stirring at room temperature the solvent is removedand the crude product obtained purified by chromatography on a silicacolumn (eluent: methylene chloride).

Spiro[(5-methoxychroman)-3,2'-[N-(2'-para-toluenesulfonylaminoethyl)pyrrolidine]]is thus obtained in a yield of 75%. ##STR76##

Infrared (KBr): 1150 cm⁻¹ ν SO₂

EXAMPLE 36:SPIRO[(5-METHOXYCHROMAN)-3,2'-[N-(4'-para-TOLUENESULFONYLAMINO-n-BUT-1'-YL)PYRROLIDINE]]

By proceeding as in Example 35 but replacingspiro[(5-methoxychroman)-3,2'-[N-(2'-aminoethyl)pyrrolidine]] withspiro[(5-methoxychroman)-3,2'-[N-(4'-amino-n-but-1'-yl)pyrrolidine]],spiro[(5-methoxychroman)-3,2'-[N-(4'-para-toluenesulfonylamino-n-but-1'-yl)pyrrolidine]]is obtained. ##STR77##

Infrared (KBr): 1150 cm⁻¹ ν SO₂

EXAMPLE 37 TO 42

By proceeding in the same way as in Example 36 but replacing tosylchloride with:

4-iodobenzoyl chloride,spiro[(5-methoxychroman)-3,2'-{N-[4'-(4'-iodobenzamido)-n-but-1'-yl]pyrrolidine}]is obtained ##STR78##

Infrared: 1620 cm⁻¹ ν C=O

4-fluorobenzoyl chloride,spiro[(5-methoxychroman)-3,2'-{N-[4'-(4'-fluorobenzamido)-n-but-1'-yl]pyrrolidine}]is obtained

Infrared: 1630 cm⁻¹ ν C=O

2-methoxybenzoyl chloride,spiro[(5-methoxychroman)-3,2'-{N-[4'-(2'-methoxybenzamido)-n-but-1'-yl]pyrrolidine}]is obtained

Infrared: 1635 cm⁻¹ ν C=O

butanoyl chloride,spiro[(5-methoxychroman)-3,2'-[N-(4'-butyramido-n-but-1'-yl)pyrrolidine]]is obtained

3-phenylpropionyl chloride,spiro[(5-methoxychroman)-3,2'-{N-[4'-(3'-phenylpropionamido)-n-but-1'-yl]pyrrolidine}]is obtained

3,4-dimethoxyphenylacetyl chloride,spiro[(5-methoxychroman)-3,2'-{N-[4'-(3',4'-dimethoxyphenyl-acetamido)-n-but-1'-yl]pyrrolidine}]is obtained.

EXAMPLE 43: SPIRO[(5-METHOXYCHROMAN) -3,2'-(N-ACETYLPYRROLIDINE)]

Add 0.253 g (2.51 mmol) of triethylamine, then, dropwise, 0.256 g (2.51mmol) of acetic anhydride to a solution of 0.5 g (2.28 mmol) ofspiro[(5-methoxychroman)-3,2'-pyrrolidine] in 10 cm³ of methylenechloride.

Stir at room temperature for 30 minutes, then concentrate at reducedpressure, take up the crude product with 10 cm³ of water and extractwith methylene chloride.

The crude oil obtained is purified by chromatography on a silica column(eluent: ethyl acetate).

0.57 g (96%) of spiro[(5-methoxychroman)-3,2'-N-acetylpyrrolidine)] arethus obtained in the form of a white solid.

Melting point: 121° C.

Infrared (KBr): 1640 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR79## 1.78 to 2.04, multiplet, 4H, H₃' and H₄ ' 2.06, singlet, 3H, H_(b)

2.52, pair of doublets J=16.6 Hz, J=2.6 Hz, 1H, H₄

3.50 to 3.63, multiplet, 2H, H₅ '

3.67, doublet J=16.6 Hz, 1H, H₄

3.76, pair of doublets J=10.2 Hz, J=2.6 Hz, 1H, H₂

3.80, singlet, 3H, H_(a)

4.96, doublet J=10.2 Hz, 1H, H₂

6.42 and 6.50, 2 doublets J=8.3 Hz, 2H, H aromatic

7.06, triplet J=8.3 Hz, 1 H, H aromatic

EXAMPLE 44: SPIRO[(5-METHOXYCHROMAN)-3,2'-(N-BENZOYLPYRROLIDINE)]

By proceeding in the same way as in Example 35, but replacing tosylchloride with benzoyl chloride andspiro[(5-methoxychroman)-3,2'-[N-(2'-aminoethyl)pyrrolidine]] withspiro[(5-methoxychroman)-3,2'-pyrrolidine)],spiro[(5-methoxychroman)-3,2'-(N-benzoylpyrrolidine)] is obtained.

EXAMPLES 45 TO 51

By proceeding in the same way as in Example 44 but replacing benzoylchloride with:

4-methoxybenzoyl chloride,spiro[(5-methoxychroman)-3,2'-[N-(4'-methoxybenzoyl)pyrrolidine]] isobtained

4-iodobenzoyl chloride,spiro[(5-methoxychroman)-3,2'-[N-(4'-iodobenzoyl)pyrrolidine]] isobtained

3-trifluoromethylbenzoyl chloride,spiro[(5-methoxychroman)-3,2'-[N-(3'-trifluoromethylbenzoyl)pyrrolidine]]is obtained

4-methylbenzoyl chloride,spiro[(5-methoxychroman)-3,2'-[N-(4'-methylbenzoyl)pyrrolidine]] isobtained

butyryl chloride, spiro[(5-methoxychroman)-3,2'-[N-butyrylpyrrolidine)]is obtained

3-phenylpropionyl chloride,spiro[(5-methoxychroman)-3,2'-[N-(3'-phenylpropionyl)pyrrolidine]] isobtained

3,4-dimethoxyphenylacetyl chloride,spiro[(5-methoxychroman)-3,2'-[N-(3',4'-dimethoxyphenyl-acetyl)pyrrolidine]]is obtained.

EXAMPLES 52 TO 53

By proceeding in the same way as in Example 4 but replacingspiro[(5-methoxychroman)-3,2'-(pyrrolidin-5'-one)] with:

spiro[(5-methoxychroman)-3,2'-[N-(4'-butyramido-n-but-1'-yl)pyrrolidine]],spiro[(5-methoxychroman)-3,2'-{N-[4-(N-n-but-1-yl)amino-n-but-1-yl]pyrrolidine}]is obtained ##STR80##spiro[(5-methoxychroman)-3,2'-{N-[4-(3,4-dimethoxy-phenylacetamido)-n-but-1-yl]pyrrolidine}],spiro-[(5-methoxychroman)-3,2'-{N-[4'-(3',4'-dimethoxy-phenethyl)amino-n-but-1'-yl]pyrrolidine}]is obtained. ##STR81##

EXAMPLE 54: SPIRO[(5-ACETYLCHROMAN)-3,2'-(N-PROPYLPYRROLIDINE)] Stage I:Spiro[(5-trifluoromethylsulfonyloxychroman)-3,2'-(N-propylpyrrolidine)]

Dissolve 1 g (4.04 mmol) ofspiro[(5-methoxychroman)-3,2'-(N-propylpyrrolidine)] in 25 cm³ ofmethylene chloride and then add 1.62 cm³ of pyridine.

Cool to 0° C. then add dropwise 0.80 cm³ of trifluoromethanesulfonicanhydride.

Continue stirring at between 0° and +5° C. for 1 hour, then extract withmethylene chloride, dry the organic phase and concentrate at reducedpressure.

The crude product is purified by chromatography on a silica column(eluent: ethyl acetate).

Spiro[(5-trifluoromethylsulfonyloxychroman)-3,2'-[N-propylpyrrolidine)]is thus obtained in a yield of 80%.

Infrared: 1405 cm⁻¹ and 1200 cm⁻¹ ν sulfonate

Stage II: Spiro[(5-acetylchroman)-3,2'-(N-propylpyrrolidine)]

Dissolve 0.8 g (2.11 mmol) ofspiro[(5-trifluoromethylsulfonyloxychroman)-3,2'-(N-propylpyrrolidine)]in 8 cm³ of N,N-dimethylformamide.

Next add 0.43 g (4.22 mmol) of triethylamine, 1.16 g (11.61 mmol) ofbutyl vinyl ether, 0.023 g (0.058 mmol) of1,2-bis(diphenylphosphino)ethane and 0.012 g (0.052 mmol) of Pd(OAc)₂,then heat to reflux for 8 hours.

After cooling, hydrolyze with 7 cm³ of 10N hydrochloric acid, stir atroom temperature for one hour and extract with methylene chloride.

After drying at reduced pressure, the crude product is purified bychromatography on a silica column (eluent: ethyl ether/petroleum ethermixture gradient).

Spiro[(5-acetylchroman)-3,2'-(N-propylpyrrolidine)] is thus obtained ina yield of 40%.

Infrared: ν C=O

EXAMPLE 55: SPIRO[(5-METHOXYCHROMAN)-3,2'-(3'-METHYLPYRROLIDIN-5'-ONE)]

By proceeding in the same way as in Example 1 but replacing methylacrylate in stage I with methyl crotonate,spiro[(5-methoxychroman)-3,2'-(3'-methyl-pyrrolidin-5'-one)] isobtained. ##STR82##

Infrared (KBr): 1665 cm⁻¹ ν C=O

EXAMPLE 56:SPIRO[(5-METHOXYCHROMAN)-3,2'-(3'-METHYL-N-PROPYLPYRROLIDINE)]

By reducing spiro[(5-methoxychroman)-3,2'-(3'-methyl-pyrrolidin-5'-one)]with borane-dimethyl sulfide according to Example 4 and then alkylatingthe spiro[(5-methoxychroman)-3,2'-3'-methylpyrrolidine)] thus obtainedwith 1-iodopropane according to Example 5,spiro[(5-methoxychroman)-3,2'-(3'-methyl-N-propylpyrrolidine)] isobtained. ##STR83##

Infrared (film): 2970 to 2810 cm⁻¹ ν CH

1580 cm⁻¹ ν C=C aromatic.

EXAMPLE 57: LEVOROTATORY ISOMER OFSPIRO[(5-METHOXY-CHROMAN)-3,2'-PYRROLIDINE]

Dissolve 1.41 g (4.05 mmol) of binaphthylphosphoric acid ((R)-(-)BNPPA)in 50 cm³ of a 90 methanol/10 methylene chloride mixture.

Add dropwise a solution of 1.27 g (5.79 mmol) ofspiro[(5-methoxychroman)-3,2'-pyrrolidine] in 6 cm³ of methanol.

Stir at room temperature for 3 hours, then dry.

The crude salt obtained is recrystallized once first from acetonitrileand then three times from ethanol. 580 mg (35%) of binaphthylphosphateof the levorotatory isomer ofspiro[(5-methoxychroman)-3,2'-pyrrolidine)] are obtained.

550 mg (0.97 mmol) of this salt are taken up in a mixture consisting of10 cm³ of an aqueous solution (2M) of aqueous ammonia and 5 cm³ of ethylacetate.

After stirring at room temperature for one hour, extract the amine withethyl acetate and then, after drying, filter it on silica (eluent: ethylacetate).

212 mg of the levorotatory isomer ofspiro[(5-methoxychroman)-3,2'-pyrrolidine] are thus obtained.

Separation efficiency: 35%

Enantiomeric purity: 99.7%

Pouvoir rotatoire [α]_(D) ²⁰ =-15° (22 mg dans 3 cm³ de chloroforme)

EXAMPLE 58: DEXTROROTATORY ISOMER OFSPIRO[(5-METHOXYCHROMAN)-3,2'-PYRROLIDINE)]

By proceeding in way similar to Example 57, the dextrorotatory isomer ofspiro[(5-methoxychroman)-3,2'-pyrrolidine] is obtained.

EXAMPLE 59: DEXTROROTATORY ISOMER OFSPIRO[(5-METHOXYCHROMAN)-3,2'-{N-[4'-(8'-AZASPIRO-[4',5']DECANE-7',9'-DION-8'-YL)-n-BUT-1'-YL]PYRROLIDINE}]

By proceeding as in Example 8 but starting with the levorotatory isomerof spiro[(5-methoxychroman)-3,2'-pyrrolidine], the dextrorotatory isomerofspiro-[(5-methoxychroman)-3,2'-{N-[4'-(8'-azaspiro[4',5']decane-7',9'-dion-8'-yl)-n-but-1'-yl]pyrrolidine}]is obtained.

Melting point of the oxalate=72° C.

Pouvoir rotatoire [α]_(D) ²⁰ =+15° (19,6 mg dans 3 cm³ de chloroforme)

EXAMPLE 60: LEVOROTATORY ISOMER OFSPIRO[(5-METHOXYCHROMAN)-3,2'-{N-[4'-(8'-AZASPIRO-[4',5']DECANE-7',9'-DION-8'-YL)-n-BUT-1'-YL]PYRROLIDINE}]

By proceeding as in Example 8 but starting with the dextrorotatoryisomer of spiro[(5-methoxychroman)-3,2'-pyrrolidine], the levorotatoryisomer ofspiro-[(5-methoxychroman)-3,2'-{N-[4'-(8'-azaspiro[4',5']-decane-7',9'-dion-8'-yl)-n-but-1'-yl]pyrrolidine}]is obtained.

Melting point of the oxalate=72° C.

Pouvoir rotatoire [α]_(D) ²⁰ =-16° (21,2 mg dans 3 cm³ de chloroforme)

EXAMPLE 61: SPIRO[(5-METHOXYCHROMAN)-3,2'-PIPERIDINE] Stage I: Ethyl3-(5-methoxy-3-nitrochroman-3-yl)-butyrate

Add 0.02 cm³ of benzyltrimethylammonium methylate and then 0.585 g (3mmol) of ethyl 4-bromobutyrate to a solution of 0.21 g (1 mmol) of.3-nitro-5-methoxychroman in 6 cm³ of N,N-dimethylformamide.

Heat to 60° C. for 15 hours, then dry at reduced pressure and purify thecrude product obtained by chromatography on a silica column (eluent:methylene chloride).

0.145 g (45%) of ethyl 3-(5-methoxy-3-nitro-chroman-3-yl)butyrate arethus obtained in the form of colorless oil.

Infrared (film): 1725 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR84## 0.94, triplet J=7.2 Hz, 3H,H_(e) 1.30 to 1.39, multiplet, 2H, H_(b)

2.10 to 2.56, multiplet, 4H, H_(a) and H_(c)

2.89 and 3.60, 2 doublets J=17.5 Hz, 2H, H₄

3.84, singlet, 3H, H_(f)

4.09 and 4.57, 2 doublets, J=11.6 Hz, 2H, H₂

4.12, quadruplet, J=7.2 Hz, 2H, H_(d)

6.47 and 6.50, 2 doublets, J=8.3 Hz, 2H, H aromatic

7.11, triplet, J=8.3 Hz, 1H, H aromatic

Stage II: Spiro[(5-methoxychroman)-3,2'-(piperidin-6'-one)]

Dissolve 0.325 g (1 mmol) of ethyl3-(5-methoxy-3-nitrochroman-3-yl)butyrate in 20 cm³ of ethanol.

Add 40 mg of Raney nickel and heat to reflux under hydrogen atmosphereovernight.

After cooling, filter the reaction mixture on celite, then after dryingthe filtrate, purify the crude product obtained by chromatography on asilica column (eluent: 5 methanol/95 methylene chloride).

0.235 g (95%) of spiro[(5-methoxychroman)-3,2'-(piperidin-6'-one)] arethus obtained in the form of a colorless oil.

Infrared (film): 3245 cm⁻¹ ν NH

1675 cm⁻¹ ν C=O

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR85## 1.48 to 1.63, multiplet, 2H, H₄' 1.90 to 2.10, multiplet, 2H, H₃ '

2.39 to 2.51, multiplet, 2H, H₅ '

2.75 to 2.87, 2 doublets, 2H, H₄

3.83, singlet, 3H, H_(a)

3.88 and 3.93, 2 doublets J=11.2 Hz, 2H, H₂

5.80, unresolved bands, 1H, NH

6.46 and 6.52, 2 doublets, J=8.3 Hz, 2H, H aromatic

7.10, triplet, J=8.3 Hz, 1H, H aromatic

Stage III: Spiro[(5-methoxychroman)-3,2'-piperidine]

Dissolve 0.25 g (1 mmol) ofspiro[(5-methoxy-chroman)-3,2'-(piperidin-6'-one)] in 15 cm³ of THF,then add the borane-dimethyl sulfide complex and heat to reflux for 4hours 30 min.

Dry the reaction mixture, take up the residue very slowly in 5 cm³ ofmethanol and then add 2.5 cm³ of 2M hydrochloric acid and heat to refluxfor 90 minutes.

After cooling, remove the methanol, neutralize with a 2M aqueous sodiumhydroxide solution, extract with methylene chloride.

The crude product obtained by drying is purified by chromatography on asilica column (eluent: 100% ethyl acetate).

0.160 g (70%) of spiro[(5-methoxychroman)-3,2'-piperidine] are thusobtained.

Infrared (film): 3300 cm⁻¹ ν NH

1580 cm⁻¹ ν C=C aromatic

¹ H NMR 300 MHz (CDCl₃) δ: ppm ##STR86## 1.31 to 1.40, multiplet, 2H, H₄' 1.56 to 1.97, multiplet, 4H, H₅ ' and H₃ '

2.19, singlet, 1H, NH

2.68, singlet, 2H, H₄

2.95 to 3.18, multiplet, 2H, H₆ '

3,81, singlet, 3H, H_(a)

3,83, singlet, 2H, H2

6.44 and 6.53, 2 doublets, J=8.3 Hz, 2H, H aromatic

7.07, triplet, J=8.3 Hz, 1H, H aromatic

EXAMPLE 62 TO 69

By proceeding as in Examples 5, 8, 13, 17, 19, 20, 22, 24 and 27, butreplacing spiro[(5-methoxychroman)-3,2'-pyrrolidine] withspiro[(5-methoxychroman)-3,2'-piperidine] the following are obtained:

spiro[(5-methoxychroman)-3,2'-(N-propylpiperidine)] ##STR87##spiro[(5-methoxychroman)-3,2'-{N-[4'-(8'-azaspiro-[4',5']decane-7',9'-dion-8'-yl)-n-but-1'-yl]piperidine}]##STR88##

Infrared (film): 1655 and 1720 cm⁻¹ ν C=O

spiro[(5-methoxychroman)-3,2'-[N-(4'-phthalimido-n-but-1'-yl)piperidine]]##STR89##

Infrared (film): 1705 cm⁻¹ ν C=O

-spiro[(5-methoxychroman)-3,2'-{N-[2'-(8'-azaspiro-[4',5']decane-7',9'-dion-8'-yl)ethyl]piperidine}]##STR90##spiro[(5-methoxychroman)-3,2'-{N-[4'-(oxazolo[4',5'-b]pyridin-2'(3H)-on-3'-yl)-n-but-1'-yl]piperidine}] ##STR91##spiro[(5-methoxychroman)-3,2'-{N-[4'-(4',4'-dimethylpiperidine-2',6'-dion-1'-yl)-n-but-1'-yl]piperidine}]##STR92##spiro[(5-methoxychroman)-3,2'-{N-[4'-(1',1'-dioxo-1',2'-benzisothiazol-3'(2H)-on-2'-yl)-n-but-1'-yl]-piperidine}]##STR93## spiro[(5-methoxychroman)-3,2'-(N-benzylpiperidine)] ##STR94##

Pharmacological Study of the Compounds of the Invention EXAMPLE 70: INVITRO DETERMINATION OF THE AFFINITY OF THE COMPOUNDS OF THE INVENTIONFOR SEROTONINERGIC, DOPAMINERGIC AND ALPHA ADRENERGIC RECEPTORS

The determinations of affinity for serotoninergic, dopaminergic andalpha adrenergic receptors were performed according to conventionaltechniques by displacement of a reference radio ligand.

    ______________________________________                                        RECEPTOR RADIOLIGAND     TISSUE USED                                          ______________________________________                                        5-HT.sub.1 A                                                                           8-OH-DPAT       Hippocampus                                          5-HT.sub.1 B                                                                           5-OH-Tryptamine Cortex + striatum +                                                           Globus Pallidus                                      5-HT.sub.1 C                                                                           N-Methyl-Mesulergine                                                                          Cortex, hippocampus                                  5-HT.sub.1 D                                                                           5-OH-Tryptamine Cortex + striatum +                                                           Globus Pallidus                                      5-HT.sub.2                                                                             Ketanserin      Cortex                                               5-HT.sub.3                                                                             BRL 43694       Area postrema                                        ______________________________________                                    

The results of these studies of binding show that the compounds of theinvention have a high affinity associated with a strong selectivity forthe 5-HT₁ A receptors when compared with other serotoninergic receptors.

This selectivity for 5-HT₁ A receptors is also very great (at least afactor of 1000) in relation to the D₁, D₂ dopaminergic and α₁, α₂adrenergic receptors.

For example,spiro[(5-methoxychroman)-3,2'-{N-[4'-(8'-azaspiro[4',5']decane-7',9'-dion-8'-yl)-n-but-1'-yl]pyrrolidine}]has a nanomolar affinity for 5HT₁ A receptors, whereas its affinity forthe other serotoninergic receptors (5-HT₁ B, 5-HT₁ C, 5-HT₁ D, 5-HT₂,5-HT₃) is between 4×10⁻⁶ M and 2×10⁻⁵ M and while its affinity for theother D₁, D₂, α₁ and α₂ receptors is less good than 10⁻⁶ M.

EXAMPLE 71: ACUTE TOXICITY STUDY

The acute toxicity was determined after oral administration ofincreasing doses (0.1, 0.25, 0.50, 0.75 and 1 g/Kg⁻¹) of the products ofthe invention to batches of five mice (20 ±2 grams).

The animals were observed at regular intervals during the first day anddaily for two weeks following the treatment. It is apparent that thecompounds of the invention are completely non-toxic. No death isobserved after the administration of a dose of 1 g.Kg⁻¹. No disorder isobserved after the administration of this dose.

EXAMPLE 72: STUDY OF THE ANTIDEPRESSANT ACTIVITY EFFECT ON ESCAPEFAILURES

The study of the products is carried out on the model of "learnedhelplessness", which consists in inducing in the animal, by a series ofuncontrollable aversive events, a defect during the subsequent avoidancetasks (Martin et al., 1986, Pharmacol. Biochem. Behav., 24, 177-181).

We use male Wistar A.F. rats obtained from CERJ homogeneous breedings,weighing between 180 and 200 grams. The animals are kept in the animalhouse for one week before the test, in plastic boxes, in groups of 10,at an ambient temperature of 21° C. ±1° C., with free access to waterand feed.

The animals are isolated in small boxes and subjected to 60 unavoidableelectric shocks (0.8 mA every minute ±15 seconds). A group of controlrats does not receive electric shocks. The capacity of the animals tocarry out an avoidance learning (shuttle-box) is assessed 48 hours laterand during 3 consecutive days. During the learning sections, the animalsundergo 2 tests per minute for 15 minutes. The number of escape failuresis noted for each rat. The animals are treated (i.p.; 0.5 ml/100 g) 6hours after the unavoidable shocks and for 4 days thereafter, in themorning 30 minutes before the shuttle-box session and the eveningbetween 6 p.m. and 7 p.m.

The test products are dissolved in distilled water.

The test products are administered at doses of 0.25 mg. kg/day. The testdemonstrates the products of the invention significantly decrease thenumber of escape failures, thereby reflecting an activity of theantidepressant type.

EXAMPLE 73: PHARMACEUTICAL COMPOSITIONS

Tablets containing 2.5-mg doses ofspiro[(5-methoxychroman)-3,2'-{N-[4'-(8'-azaspiro[4',5']decane-7',9'-dion-8-yl)-n-but-1'-yl]pyrrolidine}]

Formula for 1000 tablets:

    ______________________________________                                        Spiro [(5-methoxychroman)-3,2'-{N-[4'-(8'-                                                                2.5 g                                             azaspiro[4',5']decane-7',9'-dion-8'-yl)-                                      n-but-1'-yl]pyrrolidine}]                                                     Wheat starch                15 g                                              Corn starch                 15 g                                              Lactose                     65 g                                              Magnesium stearate          2 g                                               Silica                      1 g                                               Hydroxypropyl cellulose     2 g                                               ______________________________________                                    

We claim:
 1. A spirochroman compound selected from those of formula (I):##STR95## in which: m is 1,A denotes methylene (CH₂) R₁ denotes:(I)hydrogen, or (II) linear or branched alkyl having 1 to 6 carbon atoms,inclusive, R₂ denotes --O--(II) substituted by any one of the followinggroups: ##STR96## in which: n is 1, R₃ denotes hydrogen their opticalisomers, isolated or in mixture form, and pharmaceutically-acceptableinorganic or organic acid addition salts thereof.
 2. A compound asclaimed in claim 1, which isspiro[{5-[4-(8-azaspiro[4,5]decane-7,9-dion-8-yl)-n-butyloxy]-chroman]-3,2'-(N-propylpyrrolidine)]whose formula is shown below, its enantiomers, isolated or in mixtureform, and a salt of addition thereof to a pharmaceutically-acceptableinorganic or organic acid ##STR97##
 3. A pharmaceutical compositioncomprising as active principle an effective antidepressive or anxiolyticamount of a compound as claimed in claim 1, in combination with one ormore pharmaceutically-acceptable excipients or vehicles.
 4. A method ortreating a mammal in need of treatment afflicted with a disease selectedfrom depression and anxiety comprising the step of administering to thesaid mammal an amount of a compound of claim 1 which is effective foralleviation of symptoms of the said disease.
 5. A compound of claim 1which isspiro[{5-[4-(4,4-dimethylpiperidine-2,6-dione-1-yl)-n-but-1-yl]oxychroman}-3,2'-(N-propylpyrrolidine)]or a pharmaceutically-acceptable acid addition salt thereof.
 6. Acompound which isspiro[{5-[4-(3-azabicyclo-[3.3.0]octane-2,4-dione-3-yl)-n-but-1-yl]oxychroman}-3,2'-(N-propylpyrrolidine)]or a pharmaceutically-acceptable acid addition salt thereof.